Apparatus and method for transferring samples from a source to a target

ABSTRACT

A transfer unit for transferring a sample from a source vessel to a target vessel. The transfer unit includes a transfer device having a pin tip with a central bore terminating at a bottom wall, an actuating element movably disposed in the pin tip bore, an actuator rod for moving the actuating element and a compensating device connected between the actuating element and the actuator rod. The actuator rod moves the actuating element between a first position adjacent the tip bottom wall and a second position away from the bottom wall. Movement of the actuating element causes a sample in proximity to the pin tip to be alternately collected and released from the pin tip. Such movement also defines a stroke length for the actuator rod, wherein the compensating device compensates for any variations in the actuator rod stroke length. The transfer unit further includes a tip ejector for removing the disposable tips from the transfer device and a tip loading station for applying the tips to the transfer device.

CROSS-REFERENCE TO RELATED U.S. APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/135,962, filed on May 25, 2005.

FIELD OF THE INVENTION

The present invention relates generally to the field of analyticalseparation and combining of samples and, more particularly, to a systemand apparatus for individually actuating and controlling a multiplearray of collection members for transferring samples from a plurality ofsource vessels to a plurality of target vessels.

BACKGROUND OF THE INVENTION

Analytic and diagnostic procedures in the laboratory often require thetransfer of a plurality of samples, simultaneously, from one array ofliquid-containing wells to another. In order to transfer, add, collector combine liquids, various multi-transferring systems have beendevised. The most commonly used is a multi-pipette which collects liquidfrom an array of source wells for transfer to an array of target wells,simultaneously, by application or release of application, respectively,of vacuum force. In operation, the pipette for collecting or releasingof liquid is connected to a single vacuum source provided to all thepipettes in the system so that all samples in the array of wells arecollected and released at once.

In recent years, magnetic particles have been used for a variety ofseparation, purification, and isolation techniques in connection withchemical or biological molecules. In those techniques, a molecule iscoupled to a magnetic particle capable of forming a specific binding(hereinafter “affinity binding”) with a molecule in a biological sample,which is to be isolated, purified or separated. The biological sample isthen brought into contact with the magnetic particle and thosebiological molecules which bind to the magnetic particles are thenisolated by application of a magnetic field.

Various devices have been developed to utilize such magnetic separationtechniques in order to transfer the magnetic particles from one locationto another. Indeed, magnetic separation technology has passed throughseveral phases in the recent years. The first generation of magneticseparation technology used a two step separation technique involving aseparation stand including a magnetic plate placed directly under amicro-plate. These thirty year old simple magnetic plates were composedof permanent magnets encapsulated in plastic which would contact themicro-plate vessels containing the magnetic particle suspensions. Themagnetic particles within the suspensions would be drawn to the bottomor the inner surfaces of the wells in the micro-plate and the liquid wasdrawn out of the well or vessel leaving the magnetic particles behind.In general, such devices are termed “first generation magneticseparators.”

One drawback of the “first generation” separators relates to the factthat the stationary permanent magnets positioned below the micro-platesdo not come into direct contact with the magnetic particles due to thethickness of the plate and vessel sides. As a result, the magnetic fieldapplied to the individual micro-plate wells is relatively weak due tothe distance between the magnetic plate and the magnetic particles andseparation is, therefore, somewhat inefficient.

To overcome this drawback, the recent second generation of magneticseparators generally employ a magnetic pipette in a one step separationprocess, wherein a magnetic rod is inserted into the magnetic solutionto capture magnetic particles. Here, magnetic particles are attracted bystrong magnetic fields to the rods and then moved out of the magneticsuspension and transferred to another vessel containing fresh washingliquid or reagent solution. The rod is then demagnetized to permitdetachment of the magnetic particles into the other liquid.

Such a “second generation magnetic separator” is disclosed, for example,in U.S. Pat. No. 4,292,920. This device includes a single or multi-pinarrangement, corresponding to a micro-well arrangement, which is capableof insertion into the wells of a micro-plate to attract magneticparticles by magnetic force. In one embodiment, the pin is connected toan electromagnet, and by turning the electromagnet on and off the pinbecomes magnetized, or non-magnetized, respectively.

Another “second generation magnetic separator” is disclosed in U.S. Pat.No. 5,567,326, which shows an apparatus and method for separatingmagnetically responsive particles from a nonmagnetic test medium inwhich they are suspended. The device comprises a plurality ofnonmagnetic pins (termed “magnetic field directing elements”) arrangedin an array, and a magnet positioned normal to the array. Placing themagnet on the array of pins renders all the pins in the array magneticthereby causing particles to be attracted to them. Removing the magnetcauses the pins to become non-magnetic, and consequently the magneticparticles are released from the pins.

The drawbacks of the above “second generation separators” reside in thefact that the magnetic rods or pins come into direct contact with themagnetic particles, so that if rinsing and sterilization is required,the whole apparatus or device has to be washed. Such a procedure isexpensive and time consuming. Furthermore, even where the magnetic rodsare covered with disposable protective tips, the collection of particlesis not efficient since some of the particles remain in the suspensiondue to surface tension forces. Another drawback of these devices residein the fact that where a multi-pin device is used to collect magneticparticles from a plurality of wells, all of the pins are fixed to amovable head and travel up and down as a unit such that all of thesamples from all the wells have to be collected at once in an “all ornone” fashion. Thus, it is not possible to selectively collect particlesfrom only selected wells in an array.

In U.S. Pat. No. 6,409,925, Gombinsky et al. disclose a “thirdgeneration magnetic separator.” The '925 patent discloses a devicewherein each collecting pin can be independently controlled.Specifically, the disclosed magnetic rod design allows for a magnetdisposed therein to be freely and independently movable up or down tothereby magnetically energize and de-energize the rod. Thus, each rod isindependently magnetized regardless of the magnetization of the otherrods. This unique feature permits multiple degrees of freedom (i.e., pinhead movement and independent magnet movement) compared to “secondgeneration” systems that have only one degree of freedom.

Accordingly, it would be desirable to improve upon the latest “thirdgeneration” magnetic separator technology in various ways to provide acomplete control and actuation system that utilizes third generationtechnology. It would be further desirable to provide such a system witha selectable bottom magnet array and a combinatorial tip loader for theupper pin device.

SUMMARY OF THE INVENTION

The present invention is a control system for transferring a sample froma source vessel to a target vessel. The control system generallyincludes a vessel unit, a primary transfer unit, an x-drive, a y-drive,a z-drive and a control unit for controlling the drives. The vessel unitincludes a translatable support plate for supporting the source vesseland the target vessel thereon and the transfer unit includes at leastone transfer device for transferring the sample from the source vesselto the target vessel. The x-, y- and z-drives reciprocally translate oneof the support plate and the transfer device in a respectivex-direction, y-direction and z-direction, wherein the x, y and zdirections define a three axis Cartesian coordinate system.

The present invention may take the form of a control system wherein theprimary transfer unit comprises a primary magnet unit and the transferdevice uses a magnetic force to attract the sample thereto.Additionally, the vessel drive unit is further preferably in the form ofa micro-well drive unit including a translatable support plate forsupporting a micro-well tray having at least one of the source vesseland the target vessel thereon.

In a preferred embodiment, the primary magnet unit includes an array ofpins and a magnet actuator system for selectively applying and removingthe magnetic force at the tip of at least one pin of the pin array. Thepin further preferably includes a hollow pin body terminating in a tipand a magnet slidably disposed within the hollow pin body, wherein themagnet actuator system drives the magnet within the hollow pin body tomove from a first position adjacent the tip of the pin to a secondposition away from the tip. When the magnet is adjacent the tip, themagnetic force is applied at the tip and when the magnet is away fromthe tip, the magnetic force is removed from tip.

The magnet actuator system preferably includes an actuator plate havingat least one individually activated electromagnet disposed thereon, anactuator plate drive for reciprocally translating the actuator plate anda magnet rod having a distal end connected to the magnet in the hollowpin body. The magnet rod, which may take the form of a flexible cable,includes a ferromagnetic piston portion engageable with theelectromagnet when the electromagnetic is activated for moving themagnet from the first position to the second position upon translationof the actuator plate. Also, the actuator system further preferablyincludes a piston housing spaced from the actuator plate. The pistonhousing can include a tension spring connected to the ferromagneticpiston portion of the magnet rod for biasing the piston portion towardthe piston housing. Preferably, the piston housing includes a permanentmagnet for biasing the ferromagnetic piston toward the piston housing.

In an alternative embodiment, the magnet actuator system includes amagnet rod having a proximal end and a distal end, and an individuallyactivated magnet rod drive. The distal end of the magnet rod isconnected to the magnet in the hollow pin body and the magnet rod driveis connected to the proximal end of the magnet rod for moving the magnetfrom its first position to its second position.

The magnetic pin control system of the present invention furtherpreferably includes a secondary magnet unit including at least onesecondary magnet element supported on a secondary magnet plate, whereinthe support plate of the micro-well drive unit is disposed between thepin tip of the primary magnet unit and the secondary magnet element ofthe secondary magnet unit. The secondary magnet further preferablyincludes its own y-axis secondary magnet plate drive for reciprocallytranslating the secondary magnet plate in the y-direction and a z-axissecondary magnet plate drive for reciprocally translating the secondarymagnet plate in the z direction.

Like the pin, the secondary magnet element is preferably part of anarray of secondary magnet elements which are adapted to be selectivelyactivated and de-activated for alternately applying and removing amagnetic field at a bottom of the micro-well tray. This can be achievedwith a secondary magnet actuator system that drives a magnet slidablydisposed in a bore of the secondary magnet plate between a firstposition adjacent the micro-well support plate for applying the magneticfield to a respective well of the micro-well tray, to a second positionaway from the micro-well support plate for removing the magnetic fieldfrom the respective well of the micro-well tray. Here too, the secondarymagnet actuator preferably includes an actuator plate having at leastone individually activated electromagnet disposed thereon, an actuatorplate drive for reciprocally translating the actuator plate and a magnetrod having a distal end connected to the magnet in the secondary magnetplate, wherein the magnet rod includes a ferromagnetic piston portionengageable with the electromagnet when the electromagnetic is activatedfor moving the magnet from the first position to the second positionupon translation of the actuator plate.

The pin control system of the present invention may further include atip insertion unit for applying a disposable tip to the pin of theprimary magnet unit and a tip removal unit for removing the disposabletip from the pin. The tip insertion unit may include a block having abore formed therein. The bore has a proximal end and a distal end. Theproximal end is sized to receive the disposable tip for application tothe pin and a pressure source is connected to the distal end of the borefor applying a pressure in the bore for forcing the disposable tip outof the bore. A piston slidably received within the bore may also beprovided for forcing the disposable tip out of the bore under theinfluence of the pressure.

The tip removal unit may include a fork defined by at least one channelhaving a width corresponding to a diameter of the pin. The channel isadapted to engage the disposable tip of the pin when the pin is broughtinto the channel.

The present invention further involves a method for transporting asample from a source vessel to a target vessel. The method generallyincludes the steps of supporting the source vessel and the target vesselon a translatable support plate, translating the support plate in anx-direction to position the source vessel below a transfer device of aprimary transfer unit, translating the primary transfer unit in ay-direction to position the transfer device above the source vessel,translating the primary transfer unit in a z-direction to lower thetransfer device into the source vessel, activating the transfer deviceto collect the sample contained in the source vessel, translating theprimary transfer unit in the z-direction to raise the transfer deviceout of the source vessel, translating the primary transfer unit in they-direction to position the transfer device above the target vessel,translating the support plate in the x-direction to position the targetvessel below the transfer device of the primary transfer unit,translating the primary transfer unit in the z-direction to lower thetransfer device into the target vessel and deactivating the transferdevice to release the sample from the transfer device into the targetvessel. According to the present invention, the x, y and z directionsdescribed above define a three axis Cartesian coordinate system.

In a preferred embodiment, the primary transfer unit is in the form of aprimary magnet unit and the transfer device is in the form of a pinhaving a tip. In this case, the activating step involves the step ofapplying a magnetic force at the tip to attract magnet particles of thesample contained in the source vessel and the deactivating step involvesthe step of removing the magnetic field from the tip to release themagnet particles from the tip into the target vessel. The magnetic forceis preferably applied by moving a magnet within a hollow body of the pinto a first position adjacent the tip of the pin and the magnetic forceis removed by moving the magnet to a second position away from the pintip. Also, the step of moving the magnet to the first positionpreferably includes the steps of engaging a ferromagnetic piston portionof a magnet rod connected to the magnet with an electromagnet fixed onan actuator plate and translating the actuator plate. Preferably,movement of the piston is biased by a permanent magnet or a tensionspring.

The method of the present invention further preferably includes the stepof providing a secondary magnet unit below the translatable supportplate opposite the primary transfer unit, wherein the secondary magnetunit includes at least one secondary magnet element supported on asecondary magnet plate. The secondary magnet unit may be translated inthe y-direction and the z-direction to position the secondary magnetelement under the transfer device of the primary transfer unit.

Additionally, the secondary magnet element may be selectively activatedand de-activated for alternately applying and removing a magnetic fieldat a bottom of the translatable micro-well support plate. The step ofselectively activating and de-activating the secondary magnet elementpreferably includes the step of moving a magnet disposed within a boreof the secondary magnet plate between a first position adjacent thetranslatable micro-well support plate and a second position away fromthe translatable micro-well support plate. The magnet may be moved byengaging a ferromagnetic piston portion of a magnet rod connected to themagnet with an electromagnet fixed on an actuator plate and translatingthe actuator plate.

Moreover, the method of the present invention may further include thesteps of translating the primary magnet unit in the y-direction and thez-direction to position the pin tip adjacent a tip insertion unit andapplying a disposable tip on the pin with the tip insertion unit. Thiscan be accomplished by applying a pressure within a bore having thedisposable tip seated therein, wherein the pressure forces the tip outof the bore and onto the pin.

Furthermore, the method of the present invention may further include thesteps of translating the primary magnet unit in the y-direction and thez-direction to position the pin adjacent a tip removal unit and removinga disposable tip from the pin with the tip removal unit. This can beaccomplished by positioning the pin within a channel of a fork of thetip removal unit and lifting the pin, wherein the disposable tip engagesthe fork and is removed from the pin.

Of course, the system can also be operated by selecting any pincombination within the array permitting quantitative collection ofparticles from a given magnetic suspension. This feature of quantitativeseparation and transfer allows for dividing a sample into sub-samples.Also, the present invention allows for the sample particles to be washedefficiently with a “flip-flop” movement of particles due to magnetsmoving under the sample wells.

The present invention further involves a system for transferring samplesfrom a source vessel to a target vessel including a transfer devicehaving a hollow body and an actuating element movably disposed in thehollow body between a first and a second position. Movement of theactuating element causes a sample in proximity to the transfer device tobe alternately collected and released from the transfer device. Thesystem further includes an actuator plate having at least oneindividually activated electromagnet disposed thereon, an actuator platedrive for reciprocally translating the actuator plate and an actuatorrod having a distal end connected to the actuating element in the hollowbody of the transfer device. The actuator rod includes a ferromagneticpiston portion engageable with the electromagnet when theelectromagnetic is activated for moving the actuating element from thefirst position to the second position upon translation of the actuatorplate.

In a preferred embodiment, the transfer device of the primary transferunit includes a pin tip having a central bore terminating at a bottomwall, an actuating element movably disposed in the pin tip bore, anactuator rod for moving the actuating element and a compensating deviceconnected between the actuating element and the actuator rod. Theactuator rod moves the actuating element between a first positionadjacent the tip bottom wall and a second position away from the bottomwall. Movement of the actuating element causes a sample in proximity tothe pin tip to be alternately collected and released from the pin tip.Such movement also defines a stroke length for the actuator rod, whereinthe compensating device compensates for any variations in the actuatorrod stroke length.

Again, the actuating element is preferably a magnet for alternatelyapplying and removing a magnetic force at the pin tip. The compensatingdevice preferably urges the actuating element into contact with the pintip bottom wall at the first position. In this regard, the compensatingdevice is preferably a resilient element for biasing the actuatingelement against the pin tip bottom wall at the first position. Morespecifically, the compensating device preferably includes a tubularmember having a central bore and a spring disposed within the bore. Theactuating element is fixed at one end of the tubular member and theactuator rod movably extends into the central bore to engage the spring.

In an alternative embodiment, a tip ejector for removing the disposabletips from the transfer unit can be provided directly on the transferdevice head assembly. In particular, the transfer unit can include ahead assembly, a transfer device supported on the head assembly and atip ejector supported on the head assembly for removing a disposable tipfrom the transfer device. The tip ejector preferably includes an ejectorplate having an aperture defined by an edge and a drive supported on thehead assembly and connected to the ejector plate for moving the ejectorplate away from the head assembly. The transfer device extends throughthe aperture on the ejector plate and the aperture edge engages the tipto remove the tip from the transfer device upon movement of the ejectorplate away from the head assembly.

In another alternative embodiment, the tip loading station can include abase having a bore formed therein, a sub-base supported on an uppersurface of the base and a pressure source connected to the base. Thebore in the base has a proximal end terminating at an upper surface ofthe base and a distal end. The sub-base supports a tip for applicationto the transfer device and the pressure source is connected to thedistal end of the base bore for applying a pressure through the basebore for forcing the tip from the sub-base onto the transfer device.

The sub-base can be adapted to support a plurality of tips and can betranslatable with respect to the base to positively position the tipsover the base bore. Also, the tip loading station can further include atip cassette supported on the sub-base. The tip cassette has a boreformed therethrough, which is sized to receive the tip and also has adistal end terminating at the upper surface of the base.

The preferred embodiments of the control system as well as otherobjects, features and advantages of this invention, will be apparentfrom the following detailed description, which is to be read inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a top perspective view of the overall system formed inaccordance with the present invention.

FIG. 2 is a top perspective view of the system shown in FIG. 1 with themicro-well tray drive unit shown in greater detail.

FIG. 3 is a schematic diagram of the functional components of theprimary magnet unit and the secondary magnet unit.

FIG. 4 is a plan view of the system shown in FIG. 1 with the primarymagnet unit shown in greater detail.

FIG. 5 is a cross-sectional view of the preferred embodiment of themagnet rod actuator system of the primary magnet unit.

FIG. 6 is a top perspective view of an alternative embodiment of themagnet rod actuator system of the primary magnet unit.

FIG. 7 is a cross-sectional view of still another alternative embodimentof the magnet rod actuator system of the primary magnet unit.

FIG. 8 is a top perspective view of the system shown in FIG. 1, with thesecondary magnet unit, the tip insertion/removal station shown ingreater detail.

FIG. 9 is a general schematic diagram of the functional components ofthe preferred embodiment of the secondary magnet unit.

FIG. 10 is a cross-sectional view of the preferred embodiment of thesecondary magnet rod actuator system of the secondary magnet unit.

FIG. 11 is a block diagram of the overall system formed in accordancewith the present invention.

FIGS. 12 a and 12 b is a flow chart showing operation of the systemaccording to the present invention.

FIG. 13 is a flow chart of the homing procedure.

FIG. 14 is a flow chart of the tips loading procedure.

FIG. 15 is a flow chart of the xyz positioning procedure.

FIGS. 16 a and 16 b is a flow chart of the push/pull magnet procedure.

FIGS. 17 a and 17 b is a flow chart of the washing procedure.

FIGS. 18 a and 18 b is a flow chart of the flip/flop cycle.

FIG. 19 is a flow chart of the tip discard procedure.

FIG. 20 is a cross-sectional view of the preferred embodiment of theprimary magnet unit shown in further detail with the magnets in their upposition.

FIG. 21 is a cross-sectional view of the preferred embodiment of theprimary magnet unit shown in further detail with the magnets in theirdown position.

FIG. 22 is a cross-sectional view of the magnet, compensating device andmagnet rod shown in FIGS. 20 and 21.

FIG. 23 is a perspective view of the primary transfer unit showing apreferred embodiment of a tip ejector.

FIG. 24 is a perspective view of a preferred embodiment of a tip loadingstation.

FIG. 25 is a cross-sectional view of the tip loading station shown inFIG. 24.

FIG. 26 is a cross-sectional view of an alternative embodiment of themagnet actuator system of the present invention.

FIG. 27 is an exploded cross-sectional view of the end of the magnet rodshown in FIG. 26.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring first to FIG. 1, the pin control system 10 of the presentinvention generally includes five major functional components providedon a supporting structure or frame 12 having a plurality of legs 14 forsupporting the system 10 on a surface. The major functional componentsof the system 10 include a vessel unit 16, a primary transfer unit 18, asecondary magnet unit 20, a tip insertion/removal station 22 and acentral control unit 24.

Referring additionally to FIG. 2, the vessel unit 16 preferably includesa translatable support plate 26 and a motor 28 for reciprocallytranslating the support plate in the x-direction with respect to thesystem frame 12, as shown in FIG. 1. The translatable support plate 26supports a source vessel containing a sample to be transferred and atarget vessel to which the sample is transported. It is of courseconceivable for the support plate 26 to support multiple samples whichcan be simultaneously transported from respective source vessels torespective target vessels. In a preferred embodiment, the source andtarget vessels are defined in one or more micro-well trays 30 and thetranslatable support plate 26 is adapted to support at least one andpreferably two standard size micro-well trays having a matrix of nwells. In a preferred embodiment, the matrix of wells carries a magneticsuspension for bio-analytical processes and synthesis therein. It isalso conceivable that additional micro-well support plates 26 can beprovided on the system frame 12 depending on the system requirements.The support plate 26 further preferably has an open frame constructionso that the bottoms of the micro-well trays are accessible from below bythe secondary magnet unit 20, as will be described in further detailbelow.

The support plate 26 is engageable with a rail 32 fixed to the systemframe 12 to facilitate smooth translation back and forth in thex-direction. The micro-well motor 28 may be coupled to the plate 26 viaa belt 34 and pulley 35 arrangement, whereby the plate includes acarriage 36. The micro-well motor 28 is preferably a standard compactstepper motor. A suitable stepper motor for the present invention isFesto Product No. MTRE-ST, which is a two phase hybrid stepper motorwith an integrated power amplifier.

FIG. 3 is a schematic diagram showing the functional components of theprimary transfer unit 18 and the secondary magnet unit 20. The primarytransfer unit 18 generally includes at least one transfer device 37 fortransporting a sample from the source vessel to the target vessel.Preferably, and as will be discussed in further detail below, theprimary transfer unit 18 includes a head assembly 38 supporting an arrayof transfer devices 37, wherein each transfer device is capable of beingselectively activated to transfer samples from respective source vesselsto respective target vessels.

In a preferred embodiment, the primary transfer unit 18 is in the formof a primary magnet unit and the transfer device 37 is in the form of anarray 46 of pins 47, each having a hollow pin body 45 terminating in atip 49. As shown in FIGS. 3, 9 and 10, the tips 49 may be integral withthe hollow pin body, or, as will be discussed in further detail below,in the preferred embodiment, the tips take the form of disposable tips84, which are separable from the body of the pins.

The primary magnet unit 18 further includes an actuator system 40, ay-axis motor 42 and a z-axis motor 44. As will be explained in furtherdetail below, the multi-pin head assembly 38 is driven in the y and zdirections by the respective motor 42 and 44 to interact with themicro-well trays 30 driven in the x-direction by the micro-well driveunit 16. Thus, a three-axis Cartesian coordinate system is established.

It is to be understood that the arrangement of the x-drive 28, y-drive42 and z-drive 44 is described herein in an exemplary preferredembodiment. Those skilled in the art will appreciate that the three axisdrives may be positioned in different arrangements, wherein, forexample, the y-drive and/or the z-drive translate the support plate 26in the y-direction and/or the z-direction. Similarly, the support plate26 supporting the micro-well trays 30 may be stationary, whereas thetransfer device 37 may be provided with three-axis movement. Suchalternate drive arrangements are intended to come within the scope ofthe invention.

Returning to the preferred embodiment shown in FIG. 4, the transferdevices 37 or pins 47 are secured to a bottom leg of an angle plate 48in a conventional manner so that the pins 37,47 point downward in thez-direction. The array 46 shown in the drawings is a 4×3 array of twelvedevices/pins 37, 47, but other numbers or arrays of pins may beutilized. The upwardly extending leg of the angle plate 48 is coupled tothe y-axis motor 42 via a ball screw 50 and actuator 51. In this manner,the angle plate 48 with the pin array 46 are translatable in they-direction by the y-axis motor 42. The angle plate 48 and the y-axismotor 42 are in turn attached to a z-axis plate 52, which istranslatable in the z-direction. The angle plate 48 is preferablysupported on a rail 54 fixed to the z-axis plate 52 to permittranslation of the angle plate, and thus the pin array 46, in they-direction. Linear bearings (not shown) may be provided on the angleplate 48 to facilitate smooth translation.

The z-axis plate 52 is coupled to the z-axis motor 44 by a similar ballscrew 56, actuator 57 and rail 58 arrangement. In particular, the z-axisplate 52 is preferably, translatably supported on a rail 58 fixed to thesystem frame 12 so that the z-axis plate, along with the pin array 46,can be driven in the z-direction by the z-axis motor with respect to thesystem frame.

Referring additionally to FIG. 5, the transfer device 37 is preferablyin the form of a pin 47 having a hollow body 45 and a removable tip 84attached at an end thereof. The pin 47 further includes an actuatingelement 70 movably disposed in the body 45 between a first positionadjacent the tip 84 and a second position away from the tip. Thismovement of the actuating element 70 causes a sample in proximity to thetip 84 of the transfer device 37 to be alternately collected andreleased from the tip of the transfer device.

In a preferred embodiment, the actuating element 70 is a magnet whichapplies a magnetic force at the tip 49, 84 of the pin 47 when it ispositioned adjacent the tip to attract magnetic particles 39 suspendedin the liquids 41 contained in the wells 43 of the micro-well tray 30,as shown in FIG. 3. When the magnet 70 is retracted or withdrawn awayfrom the tip 49, 84 of the pin 47, the magnetic force is thereby removedand the magnetic particles 39 are released from the tip. Thisinteraction between the magnet rods 66 and the pins 47 and the resultingmagnetic operation of the pin array 46 is further described in U.S. Pat.No. 6,409,925 to Gombinsky et al., the disclosure of which isincorporated herein by reference.

In an alternative embodiment, the actuating element may take the form ofa piston or a plunger which alternately creates a positive pressure or asuction within the hollow body 45. Such positive pressure may be used todischarge a sample 41 from an opening at the tip of the transfer device.Conversely, such suction may be used to draw in a sample through anopening of the tip. This operation is similar to that of a conventionalsyringe, pipette, or other known device for supplying and/or releasing avacuum.

In either embodiment, individual movement of the actuating elements 70with respect to the pins 37, 47 is controlled by the actuator 40. Such“combinatorial” movement can be achieved pneumatically, wherein each pin37,47 is connected to air lines for the supplying and release ofpneumatic forces to move the actuating elements 70 as desired.Alternatively, solenoid valve-equipped pipettes, instead of magnets canalso be used with the present invention for the transportation of beads.However, in a preferred embodiment, movement of the actuating elements70 is achieved through an electronically controlled clutch-typemechanism, as will be described in further detail below.

In the preferred embodiment, the transfer device actuator system 40includes an actuator plate 60 fixed to a linear drive 62, such as apneumatic actuator, via one or more piston rods 64 or other form ofconnection for reciprocally translating the actuator plate in thez-direction. The linear drive 62 is preferably a pneumatic cylinderconnected to inlet and outlet air lines and in electrical communicationwith the central control unit 24. The actuator plate 60 includes aplurality of individually activated electromagnets 61 fixed thereon. Thenumber and arrangement of the electromagnets 61 preferably matches thenumber and arrangement of pins 37, 47 in the multi-pin array 46. Theelectromagnets 61 each include an interior bore to translatably receivean actuator rod 66 having the actuating element 70 attached at an endthereof.

The actuator rod 66 may be a semi-rigid tubular member orientedvertically with respect to the pins 37, 47, as shown in FIG. 5, or therod may take the form of a flexible cable enclosed in a flexible cableguide 63, allowing for more condensed and angular orientations of theactuator system 40, as shown in FIG. 6. In both embodiments, at theirends opposite the actuating element 70, the actuator rods 66 are eachfixed to a ferromagnetic piston 65 slidably received in a respectivebore 67 of a piston housing 69. Also disposed in each bore 67 of thepiston housing 69 is a tension spring 71 connected between the housingand the ferromagnetic piston 65 to maintain the actuator rod 66 in anupward retracted position.

In operation, the individual transfer devices 37 to be activated arepreferably selected with the control unit 24. Alternatively, selectionmay be made via a control pad 68 disposed on the piston housing 69. Thecontrol pad 68 may be fixed to the piston housing 69, as shown in FIG.4, or it may be provided on the frame 12 or other convenient location.The respective electromagnets 61 for the selected devices/pins 37, 47may be electrically activated, whereby an attractive magnetic force isimposed on the selected electromagnets. Specifically, the linear drive62 is activated to bring the actuator plate 60, along with the energizedelectromagnets 61, toward the ferromagnetic pistons 65 disposed in thepiston housing 69. As the actuator plate 60 nears the piston housing 69,the energized electromagnets 61 attract their respective ferromagneticpistons 65 drawing the pistons into contact with the electromagnetsagainst the tension force of the spring 71.

The linear drive 62 is then reversed wherein the actuator plate 60 isdriven away from the piston housing 69 in the z-direction. As theactuator plate 60 moves away from the piston housing 69, only thoseferromagnetic pistons 65 that have been magnetically drawn into contactwith a respective electromagnet 61 are moved together with the actuatorplate. In this regard, the magnetic force applied by the electromagnets61 is greater than the tension force applied by the tension springs 71so that the selected ferromagnetic pistons 65 will move together withthe actuator plate 60. This movement, in turn, moves the actuatingelement 70 disposed at the opposite end of the actuator rod 66 towardthe tip of its respective pin, thereby applying a magnetic force at thetip.

The remaining non-selected pistons 65 maintain their original positionswithin with the piston housing 69 by virtue of the tension force appliedby the tension springs 71. Thus, the actuating elements 70 in therespective pins 47 of the non-selected pistons 65 will not move towardthe pin tip, thereby leaving these tips without a magnetic force.

FIG. 7 shows yet another alternative embodiment for achieving this“combinatorial” technique. In this embodiment, rather than using anelectromagnet clutch-type mechanism, as described above, each actuatorrod 66 is coupled to its own individually activated rod drive 73 via apiston 75. The remaining components are the same in that a cylindricalactuating element 70, such as a magnet, is slidingly disposed in arespective pin 47 and the magnet is connected to an actuator rod 66,which in this case is preferably a flexible cable encased within aflexible cable guide 63. A magnet or iron piston 77 may be providedbetween the magnet 70 and the flexible rod 66 to improve stability. Therod drive 73 may be a pneumatic linear drive-type cylinder, as describedabove, and is preferably controlled by the system controller 24 toselectively drive the rod 66 to move the magnet 70 toward and away fromthe pin tip 84 to alternately apply and remove the magnetic force.

The present invention contemplates the use of any one of thecombinatorial techniques described herein for the primary magnet unit 18and, as will be discussed in further detail below, for the secondarymagnet unit 20. Also, as mentioned above, the system of the presentinvention would also work to individually control the primary magnetcombinatorial technique described in U.S. Pat. No. 6,409,925 toGombinsky et al.

Returning now to FIG. 3, and referring additionally to FIG. 8, in oneembodiment, the secondary magnet unit 20 includes an array of secondarymagnet elements, such as permanent magnets 72 fixed on a movablesecondary magnet plate 74. The spacing and arrangement of the permanentmagnets 72 generally coincides with the spacing and arrangement of thearray 46 of pins 47 of the primary magnet unit 18. Thus, in thedrawings, a 4×3 array of twelve permanent magnets 72, matching thespacing and arrangement of the pins 47, is provided in the secondarymagnet plate 74. A y-axis magnet plate drive 76 and a z-axis magnetplate drive 78 are connected to the secondary magnet plate 74 torespectively, reciprocally translate the magnet plate in the y andz-directions. The magnet plate drives 76 and 78 are preferably pneumaticcylinders connected to inlet and outlet air lines and in electricalcommunication with the central control unit 24.

In operation, the magnet plate 74 is controlled to move in acomplementary manner with the movement of the pin array 46 of theprimary magnet unit 18. Briefly, the magnet plate 74 is fixed in thex-direction in aligned orientation with the magnet pin array 46 and willgenerally translate together with the pin array in the y-direction sothat each well of the micro-tray 30 having a pin positioned thereoverwill also have a permanent magnet 72 positioned therebelow. Moreover, aswill be described in further detail below, the magnet plate 74 is alsocontrolled to complement the movement of the magnet rods 66 in thez-direction within the pin array 46 to facilitate removal or “washing”of the magnetic particles from the pin tips. This “washing” technique isalso described in U.S. Pat. No. 6,409,925 to Gombinsky et al., thedisclosure of which is incorporated herein by reference.

Alternatively, the secondary magnet plate 74 can be fixed in thez-direction and the permanent magnets 72 can be replaced withelectro-magnets which are selectively activated and de-activated for thealternate application of a magnetic field on the magnetic particles inthe wells of the micro-plate 30.

As mentioned above, in the preferred embodiment, the secondary magnetunit can be designed similar to the primary magnet unit 18, whereinindividual secondary magnet rods can be selected in a manner similar tothe primary magnet unit. Referring now to FIG. 9, which is a schematicdiagram showing the functional components of the preferred embodiment ofa secondary magnet unit 20′, the secondary magnet plate 74 in this caseincludes an array of cylindrical bores 100 supporting a correspondingarray of slidable secondary magnet rods 102, each having a magnet 104fixed to a distal end thereof. Like the array of permanent magnets 72described above, the array of slidable magnet rods 102 preferablymatches, in number and arrangement, the array of pins 47 of themulti-pin array 46.

With the magnet plate 74 positioned below the micro-well tray 30 by they- and z-drives 76 and 78, as described above, the magnet rods 102 areselectively controlled by a secondary magnet actuator 106. When a magnetrod 102 is fully inserted into its respective bore 100, a magnetic fieldis applied to attract the magnetic particles 39 suspended in the liquids41 contained in the wells 43 of the micro-well tray 30 adjacent theinserted magnet rod. When the magnet rod 102 is retracted or withdrawn,the magnet 104 moves away from the bottom of the micro-well tray 30,thereby releasing the magnetic particles 39 free at the bottom of thewell 43, ready to be picked up (or not) by a specifically chosen pin tip49.

As mentioned above, individual movement of the magnet rods 102 withrespect to the secondary magnet plate 74 is controlled by the secondarymagnet actuator 106. Again, such movement can be achieved pneumatically,wherein each cylindrical bore 100 in the magnet plate 74 is connected toair lines for the supplying and release of pneumatic forces to move themagnet rods 102 as desired. However, in a preferred embodiment, thesecondary magnet unit 20′ utilizes an electromagnetic clutch-typemechanism, as described above with respect to the primary magnet unit 18and as shown in FIG. 10.

Specifically, as shown in FIG. 10, the secondary magnet actuator 106generally includes an actuator plate 108 fixed to a linear drive 110,such as a pneumatic actuator, via one or more piston rods 114 or otherform of connection for reciprocally translating the actuator plate inthe z-direction. The linear drive 110 is preferably a pneumatic cylinderconnected to inlet and outlet air lines and in electrical communicationwith the central control unit 24. The actuator plate 108 includes aplurality of individually activated electromagnets 116 fixed thereon.The number and arrangement of the electromagnets 116 matches the numberand arrangement of secondary magnets 104 of the secondary magnet unit20′. The electromagnets 116 each include an interior bore 118 totranslatably receive a respective secondary magnet rod 102 having asecondary magnet 104 attached at an end thereof.

The magnet rod 102 may be a semi-rigid tubular member orientedvertically with respect to the pins 47, as shown in FIG. 10, or the rodmay take the form of a flexible cable enclosed in a flexible cable guideallowing for more condensed and angular orientations of the actuatorsystem. In any event, at their ends opposite the magnet 104, the magnetrods 102 are each fixed to a ferromagnetic piston 120 slidably receivedin a respective bore 122 of a piston housing 124. Also disposed in eachbore 122 of the piston housing 124 is a tension spring 126 connectedbetween the housing and the ferromagnetic piston 120 to maintain themagnet rod 102 in a downward retracted position.

In operation, application of a magnetic force to individual wells 43 ofthe micro-well plate 30 may be selected via a control pad 128 disposedon the piston housing 124. The respective electromagnets 116 a for theselected secondary magnets 104 are then electrically activated, wherebyan attractive magnetic force is imposed on the selected electromagnets.The linear drive 110 is then activated to bring the actuator plate 108,along with the energized electromagnets 116, toward the ferromagneticpistons 120 disposed in the piston housing 124. As the actuator plate108 nears the piston housing 124, the energized electromagnets 116 aattract their respective ferromagnetic pistons 120 a drawing the pistonsinto contact with the electromagnets against the tension force of thespring 126.

The linear drive 110 is then reversed wherein the actuator plate 108 isdriven away from the piston housing 124 in the z-direction. As theactuator plate 108 moves away from the piston housing 124, only thoseferromagnetic pistons 120 a that have been magnetically drawn intocontact with a respective electromagnet 116 a are moved together withthe actuator plate. In this regard, the magnetic force applied by theelectromagnets 116 a is greater than the tension force applied by thetension springs 126 so that the selected ferromagnetic pistons 120 awill move together with the actuator plate 108. This movement, in turn,moves the secondary magnet 104 disposed at the opposite end of themagnet rod 102 toward the micro-well plate 30, thereby applying amagnetic force at the adjacent well 43.

The remaining non-selected pistons 120 b maintain their originalpositions within the piston housing 124 by virtue of the tension forceapplied by the tension springs 126. Thus, the magnets 104 of thenon-selected pistons 120 b will not move toward the micro-well tray 30,thereby leaving these adjacent wells 43 without a magnetic force.

In all of the above embodiments, movement in the z-direction of thesecondary magnets 72 or 104 below the micro-well plates 30, inconjunction with movement in the z-direction of the multi-pin head 46has the desired effect of removing or “washing” the magnetic particles39 from the pin tips. This so called “washing” involves the dipping andraising of the pins 47 into and out of the wells 43 of the micro-plate30 both with and without the magnetic rods 66 inserted into the pins.The secondary magnets 72 or 104 can also be selected with regard to sizeand strength so that the described up and down motion will create aconcentrated “button” of separated magnetic particles 39 to gather atthe bottom of the selected wells 43.

Returning to FIG. 8, the tip insertion/removal station 22 will now bedescribed. In general, the tip insertion/removal station includes a tipinsertion unit 79 for applying the disposable tips 84 to the ends of thepins 47 of the multi-pin array 46 and a tip removal unit 81 for removingthe tips from the pins after use.

The tip insertion unit 79 generally includes a manifold block 80 fixedto the system frame 12 and having an array of cylindrical bores 82formed therethrough. The spacing and arrangement of the bores 82coincides with the spacing and arrangement of the pins 47 within the pinarray 46 of the primary magnet unit 18. Thus, in the drawings a 4×3array of twelve cylindrical bores 82, matching the spacing andarrangement of the pins 47, is provided in the manifold block. Thecylindrical bores 82 are also sized to respectively receive a disposableprotective tip 84 which is insertable and removable from a respectivepin 47 of the primary magnet unit 18. The tips 84 are loaded into thecylindrical bores 82 at the top face 86 of the manifold block 80 so thattheir tapered ends point downward.

The manifold block 80 may be loaded manually with a plurality of pintips 84 or the tip loading may be automated either by feeding single pintips into the cylindrical bores 82 or by exchanging a complete manifoldblock with pin tips pre-loaded. For example, the pin tips 84 may bemarshaled from a batch, wherein single oriented tips are fed torespective cylindrical bores 84 in the block 80, by a conventionalvibratory feeder connected to the manifold block. Alternatively, theentire manifold block 80 with spent tips 84 can be exchanged with a newblock by a small robot. In this manner, the block 80 can be pre-loadedaway from the system and kept sterile until just prior to use. Thismethod further eliminates down time of the system for loading tips. Ineither case, the system is thus provided with a higher efficiency.

Connected to each cylindrical bore 82 at the bottom face 88 of themanifold block 80 is an air supply line 90 connected at its opposite endto an air supply source (not shown) for supplying at least a positiveair pressure to the cylindrical bore. Furthermore, a tip loading piston91 is slidably disposed within each cylindrical bore 82 to force thetips 84 onto their respective pins 47 during tip insertion. Preferably,selection of the tips to be loaded is made via the central control unit24. Alternatively, a tip selection control pad 92 can be provided on themanifold block 80 to select which tip loading pistons 91 within thecylindrical bores 82 are to be activated with air pressure. The airstream is preferably guided through a special tube to preventcontamination of tips and plates.

The air supply line 90 and air supply source may be configured to alsoprovide a negative pressure or vacuum to the cylindrical bore 82 to aidin tip removal from the pins 47. In such a case, the bore 82 must becleaned and disinfected prior to reloading with clean tips.

Alternatively, the tip insertion/removal unit 22 may further include atip removal fork 94 attached to the manifold block 80 or to the systemframe. The tip removal fork 94 includes a plurality of open channels 96facing in the y-direction toward the pin array 46 of the primary magnetunit 18. The number of channels 96 provided in the fork 94 correspondsto the number of rows of pins 47 oriented in the y-direction of the pinhead 46. The width of the channels 96 is slightly larger than thediameter of the pins 47, but slightly smaller than an upper rim 85 ofthe disposable plastic tips 84 inserted on the pins.

In operation, the manifold block 80 is first manually or automaticallyloaded with a plurality of pin tips 84. Alternatively, a new pre-loadedblock 80 can be installed on the system frame 12. The pin array 46 ofthe primary magnet unit 18 is positioned above the manifold block by they and z stepper motors 42 and 44 and then gently brought down in thez-direction until the ends of the pins 47 are in close proximity to thedisposable tips 84. The desired tips 84 can then be entered in thecontrol unit 24, whereby a burst of air pressure supplied by therespective air lines 90 will drive the selected tip loading pistons 91upwardly to frictionally engage the tips 84 onto the pins 47. To releasethe air, so that the tips will not become contaminated, a special tubeis connected to the bore 82 beneath piston 91 when at its upperposition.

For removal of tips 84 from the pins 47, a negative pressure or vacuumcan be provided through the air line 90 for pulling the tips off thepins when the pin array 46 is positioned over the manifold block 80.However, in the preferred embodiment, a separate tip removal unit 81 isprovided. The tip removal unit 81 includes a tip removal fork 94 havinga plurality of channels 96 generally matching in width to the diameterof the pins 47 of the pin array 46. The pin array 46 is brought intoengagement with the tip removal fork 94, whereby individual rows of pins47 are received within the channels 96 of the fork and such that thetips 84 are positioned below the fork. The pin array 46 is then elevatedin the z-direction, whereby the fork 94 will contact the upper rim ofthe tips 84 preventing the tips from moving further along with theirrespective pins 47. A tip receptacle 98 can be provided below the tipremoval fork 94 to catch the tips 84 removed from the pins 47 in thismanner.

The last major functional component of the multi-pin system 10 of thepresent invention is the central control unit 24. The central controlunit 24 is generally a programmable controller that coordinates allmovements and actuations of the system. preferably, the central controlunit 24 controlling the system includes a programmable logic controller(PLC) with a human machine interface (HMI) and a position controller,which may be provided directly on the frame 12 or be remotely located.The control system not only handles the positioning task of moving themulti-pin head 46 to selected regions or zones within a selectedmicro-plate, it also provides the operator with the option to select auser defined combination of pins 47 for the process. Execution of allsub-processes can also be initiated individually or the entire magneticseparation process can be executed via the control system 24. Allrequired user parameters/specifications for each the above mentionedprocesses are defined by the operator via the HMI.

In a preferred embodiment, the control system 24 is a Programmable LogicController (PS1 Modular) together with a Front End display unit(FED-120C) as the HMI, supplied by Festo Corporation of Hauppauge, N.Y.The PS1 programmable logic controller communicates over a serialinterface with a position controller (Festo SPC200), transferring thepositioning data which controls the stepper motors. The Festo SPC200 isa modular position controller capable of both servo pneumatic controland stepper motor control. Three stepper motor cards are employed in thecontroller and the three axis system operates in open loop mode (withoutencoder feedback).

All operator settings are specified at the HMI device. The settingsinclude specifying the x, y and z coordinates for a specific movement, ahoming sequence, a setup menu where the number of cycles, combinatorialselection of tips, zones of the micro-plate to be used and themicro-plate selection. Other functions include a jogging function and anoption to reset the system to default/factory settings.

Referring now to FIG. 11, which is a block diagram of the overall system10, and additionally to FIGS. 12 a and 12 b, which is an operationalflow chart of the overall system, operation of the pin system will bedescribed in further detail. On power up of the system 10, the operatoris prompted to initialize (execute a reference run) the axes prior toproceeding with the main menu/entering of process parameters. Referringadditionally to FIG. 13, the “homing process” involves the stepper motorcontroller executing a reference run on all three axes at a user definedspeed. Limit or over-travel sensors 29 may be mounted on each end ofeach axis for use in the homing process. (See FIGS. 2 and 4.) Thus,“Home” can be defined by the limit switch 29 at the end of the axeswhere the motor is mounted.

Referring to FIG. 14, the next sub-process that is executed in acomplete separation cycle is the “tip loading process.” The axes arepreferably brought to their home positions prior to executing theloading of tips 84 on the pins 47. As mentioned above, the pins 47 to beloaded with tips will be specified on the HMI via the tip selection pad92. The position coordinates of the tip loading station 79 arepreferably preset and can not be changed by the operator. Once the multipin head 46 is in position and lowered into the tip loading station 79,the tip loading pistons 91 (which initially reside at the bottom 88 ofthe bores 82 of the manifold block 80) corresponding to the selectedpins are extended thereby loading the tips 84 firmly onto the selectedpins 47. The multi-pin array 46 of the primary magnet unit 18 is thenraised to its home position and the tip loading pistons 91 areretracted.

Once the tips 84 are loaded, the multi-pin head 46 will move to aspecified zone on a selected micro-plate 30 by executing an xyzpositioning sequence, as shown in FIG. 15, wherein the xy positioning isbased on “Zone” or “Well” positions. Specifically, the micro-plate 30 isdivided into a plurality of zones, each zone having a well arraycorresponding to the size and arrangement of the pin array 46. Thus, inthe embodiment shown in the drawings, the micro-well plate 30 will bedivided into a plurality of zones, wherein each zone has a 4×3 matrix ofwells and an assigned location.

Prior to positioning, the operator is preferably prompted to select thetray number, zone within that tray and the corresponding wells withinthe zone. Based on the selected tray, zone and wells, the positioningcoordinates for the x and y axis are calculated by the PLC andtransferred to the position controller via the serial interface.Initializing the positioning task and coordinating the movements(interlocks) between the axes is achieved by using handshaking signals(Start/Motion complete) and discrete I/O signals of the positioncontroller. Positioning instructions refer to the positions transferredto the position controller over the serial interface and instructions tobe executed are selected using the discrete I/O (Record select mode).

The z-axis positioning of the multi-pin head 46 can be specified inmillimeters (mm) by the operator as the well depth can differ fromdifferent micro-plate suppliers. Liquid levels can also vary within thewells. Moreover, the speeds for each axis can also be specified by theoperator in mm/s.

The execution of the movement starts with the multi-pin head 46retracting in the z-direction to a predefined (factory preset) positionto ensure the pins 47 will clear the surface of the micro-plate 30. Themicro-well drive unit 16 then positions the micro-well plate 30 in thex-direction while the y-motor 42 of the primary magnet unit 18 positionsthe multi-pin head 46 in the y-direction. The same positioning sequenceapplies to both moving the multi-pin head 46 to a sample micro-well trayand moving the head to a separate washing liquid tray. The sequences arepreferably interlocked by the handshaking signals of the positioncontroller.

Referring now additionally to FIGS. 16 a and 16 b, the next sequence,termed the “push/pull magnet sequence” essentially involves theselection of pins 47 within the multi-pin head 46 and the insertion ofthe selected magnetic rods 66 into these pins by the multi-pin actuator40. As described above, and shown in FIG. 5, in the preferredembodiment, this process is achieved by the actuation of the doubleacting cylinder 62 which lifts and lowers an actuator plate 60 having anarray of electromagnets 61 provided thereon. The default state of themulti-pin head would be with the cylinder extended where theelectromagnet array is held away from the mechanical coils 71 which holdthe magnetic rods 66 in their default position.

The push/pull process is activated by retracting the double actingcylinder 62, raising the electromagnet array 61 towards the supportingpiston housing 69. The selected electromagnets 61 draw their respectiveferromagnetic pistons 65 out of the piston housing 69 (overcoming themechanical spring force which keeps the magnetic rods 66 in their homeposition) and the rods are then inserted into the hollow pins 47. Thedouble acting cylinder 62 is also preferably fitted with two limitswitches (not shown).

Referring now additionally to FIGS. 17 a and 17 b, the “washingprocedure” generally involves the moving of the multi-pin head, withmagnetic particles attached to the selected tips, to a target zone ofthe micro-well plate or to another plate altogether. Briefly, themulti-pin head 46 is moved in the z-direction to repeatedly dip andraise the pin tips 49, 84 into and out of the micro-wells containing a“washing” fluid therein. At the same time, the magnetic rods 66 areretracted from inside the pins 47, thereby removing the magnetic forcefrom the tips. In this manner, the magnetic particles are released fromthe ends of the pins 47 and are captured by the “washing” fluid withinthe micro-wells.

As discussed above, both the “push/pull” sequence and the “washingprocedure” may further involve a “flip/flop cycle” which makes use ofthe secondary magnet unit 20. Referring now additionally to FIGS. 18 aand 18 b, the “flip/flop cycle” generally involves coordinated movementand actuation of the primary magnet unit 18 and the secondary magnetunit 20 from above and below the micro-well tray 30. Essentially, thesecondary magnet unit 20 is brought up to the micro-well tray 30 as theprimary magnet unit 18 is lifted upwardly away from the tray so that themagnets of the secondary magnet unit will help retain magnetic particlesin the micro-well trays that have not been selected. As also discussedabove, this process is further enhanced when the secondary magnet unit20 is provided with “combinatorial” capabilities, wherein individualsecondary magnets can be independently actuated, as described above andshown in FIG. 10.

Once a magnet separation process is complete, the tip discard procedurecan be initiated, as shown in FIG. 19. As discussed above, the tipdiscard procedure generally involves moving the multi-pin head 46 intoengagement with the tip removal fork 94 and elevating the head in thez-direction, whereby the fork will disengage the tips from the pins tobe captured in the tip receptacle 98.

Turning now to FIGS. 20-22, a preferred embodiment of the primary magnetunit 18 is shown in further detail. As discussed above, the primarymagnet unit 18 includes an array of pins 47 supported in a head assembly38. Each pin 47 includes a hollow pin body 45 having one end securedwithin a respective bore 202 formed in the head assembly 38. Removablyattached to the opposite end of the hollow pin body 45 is a disposabletip 84. An actuating element 70, which, in this embodiment, is apermanent magnet, is movably disposed within the hollow pin body 45between an “up” position, as shown in FIG. 20, to a “down” position, asshown in FIG. 21. In its down position, the magnet 70 is positioned atthe end of the disposable tip 84 to apply a magnetic force through thetip. When the magnet 70 is moved to its up position, as shown in FIG.20, the magnetic force applied by the magnet is removed from the tip.

The magnet 70 is driven between its up and down position by the magnetactuator system 40, as described above. In particular, selectiveactivation of individual electromagnets 61 causes the selectedelectromagnet to magnetically engage a respective ferromagnetic piston65 fixed to an end of an actuator rod 66, also termed a magnet rod. Asthe actuator plate 60 moves the electromagnets 61 downward, all of themagnetically engaged pistons 65 and associated actuator rods 66 are alsobrought downward, whereby selected magnets 70 are moved into their downposition.

In a preferred embodiment, each magnet rod 66 is connected to arespective magnet 70 via a compensating device 204. In general, thecompensating device 204 compensates for any variations in the strokelength of the magnet rod 66 so that intimate contact between the magnet70 and the bottom wall 206 of the disposable tip 84 is maintained whenthe magnet is in its down position. More specifically, as the magnetactuator system 40 drives the magnet rod 66 downward, as shown in FIG.21, the compensating device 204 will transfer the downward force fromthe magnet rod to the magnet 70 to move the magnet into its downposition, wherein the magnet comes into contact with the bottom 206 ofthe disposable tip 84. Once the magnet 70 makes contact with the bottom206 of the tip 84, any further downward movement of the magnet rod 66will be absorbed by the compensating device 204 so that the magnet willnot break through the tip bottom.

The compensating device 204 can take various forms. In simplest terms,the compensating device 204 is preferably a resilient element whichurges or biases the magnet 70 against the bottom 206 of the disposabletip 84 and can absorb downward motion of the magnet rod 66 so that themagnet does not break through the tip bottom. In this regard, thecompensating device 204 can simply consist of a solid resilientcushioning material, for example, disposed between the magnet 70 and themagnet rod 66.

However, in a preferred embodiment, the compensating device 204 includesa tubular member 208 having a central bore 210 and a spring 212 disposedwithin the central bore, as shown in FIG. 22. The tubular member 208 canbe open ended, or the central bore 210 can be separated into twoportions by an integral wall 213, as shown in FIG. 22. The magnet 70 isfixed to one end of the tubular member 208 and the magnet rod 66 ismovably attached at the opposite end of the tubular member so that theend of the magnet rod engages the spring 212 disposed within the bore210 of the tubular member. To facilitate attachment of the magnet rod 66to the compensating device 204, the tubular member 208 can include abushing 214 fixed at an open end thereof, opposite the magnet 70, forslidably receiving the outer surface of the magnet rod. Also, the magnetrod 66 can include a shoulder 216 disposed at its end, which is capturedwithin the central bore 210 of the tubular member by the bushing 214.The shoulder 216 preferably has a size enabling it to compress thespring 212 upon downward movement of the magnet rod 66. In thisembodiment, the compensating device 204 is a self-contained unit, whichis easily extracted, should it have to be replaced or cleaned, andinterchangeable with other magnet rods 66.

In use, when the magnet 70 reaches the bottom 206 of the tip 84, anyfurther downward motion of the magnet rod 66 will depress the spring 212disposed within the central bore 210 of the tubular member 208. In thisregard, the spring 212 is preferably sized to exert a force on thebottom 206 of the tip 84 which is less than the force required to removethe tip from the pin body 45. For example, if it is found that thepressure required to remove the plastic tip 84 from the hollow pin body45 is at least 400 to 500 grams, a suitable spring 212 exerting apressure of about 50 grams should be selected for use in thecompensating device 204 of the present invention. As a result, thespring 212 will allow the magnet 70 to be completely pressed (and remainin place) against the bottom 206 of the tip 84, but not beyond.

It has been found that such intimate contact between the magnet 70 andthe bottom 206 of the tip 84 provides the greatest efficiency inmagnetic particle attraction. The thickness of the bottom 206 of the tip84 is preferably about 30 microns and any gap between the magnet 70 andthe bottom of the tip will proportionately increase the distance betweenthe magnet and the magnetic particles, resulting in a decrease ofefficiency in magnetic particle attraction.

Also shown in FIGS. 20-21, and additionally in FIG. 23, is analternative embodiment of a tip ejector 220. Thus, instead of providinga separate tip insertion/removal station 22, as described above, a tipejector 220 can be provided directly on the head assembly 38 of theprimary magnet unit 18. The tip ejector 220 preferably includes anejector plate 222 and at least one pneumatic drive 224 secured to thehead assembly 38 for moving the ejector plate toward and away from thehead assembly. The ejector plate 222 has a plurality of holes orapertures 226 matching in number and arrangement with the pins 47. Eachhole 226 has a diameter slightly larger than the diameter of the pinbody 45, but is slightly smaller than the diameter of the upper rim 85of the disposable tip 84. The ejector plate 222 is preferably connectedon opposite sides with two pneumatic cylinder drives 224 fixed to thehead assembly. The ejector plate 222 is positioned so that each of theholes 226 has a respective pin 47 received therein.

In use, the ejector plate 222 is kept in an upward position toward thehead assembly 38 during operation of the primary magnet unit 18. Oncesample transfer operations are complete, the pneumatic drives 224 areactivated to move the ejector plate 222 downward away from the headassembly 38. Since the holes 226 in the ejector plate are smaller thanthe dimension of the tip rim 85, as the ejector plate moves downward,the edges of the plate surrounding the holes will make contact with therims of the tips and force the tips downward off the pin bodies 45. Asdescribed above, a tip receptacle 98 can be provided to catch thedisposed tips 84 removed from the pin bodies 45 by the ejector 220.

FIGS. 24 and 25 additionally show an alternative embodiment of a tiploading station 230. The tip loading station 230 is generally similar tothe tip insertion unit 79, described above, for applying the disposabletips 84 to the ends of the pins 47 of the multi-pin array 46. Thus, likethe tip insertion unit 79, the tip loading station 230 includes a base232 fixed to the system frame 12 and having an array of cylindricalbores 234 formed therethrough. The spacing and arrangement of the bores234 coincides with the spacing and arrangement of the pins 47 supportedon the head assembly 38 of the primary magnet unit 18. Thus, in thedrawings a 4×3 array of twelve cylindrical bores 234, matching thespacing and arrangement of the pins 47, is provided in the base 232.

Connected to each cylindrical bore 234 is an air supply connector 236,which is connected to an air supply source (not shown) for supplying apositive air pressure to the cylindrical bore. Furthermore, a tiploading piston 238 is slidably disposed within each cylindrical bore 234to force the tips 84 onto their respective pins 47 during tip insertion,as will be described in further detail below. As discussed above,selection of the tips to be loaded can be made via the central controlunit 24 or a tip selection control pad 92 provided separate from thecentral control unit.

Disposed above the base 232 is a sub-base 240, which supports at leastone tip cassette 242. The sub-base 240 preferably includes a cassettepocket 241 formed through the sub-base for receiving the tip cassette242. Thus, the pocket 241 positively positions the tip cassette 242 withrespect to the sub-base 240. Preferably, the sub-base 240 includes acontinuous pocket 241 or a plurality of pockets to positively position aplurality of tip cassettes 242. FIG. 24 shows four tip cassettes 242removably retained and positively positioned on top of the sub-base 240by way of retaining clips 246. It is conceivable that other structurecan be utilized to position and retain the tip cassettes.

The sub-base 240 is preferably linearly translatable with respect to thetip insertion base 232 to accurately position each tip cassette 242 overthe piston bores 234 formed in the base. The sub-base 240 can be madetranslatable with respect to the base 232 via a cooperating railstructure 248. The sub-base 240 can slide manually along the rail 248,or a drive unit (not shown) can be provided to move the sub-base. Ineither case, the sub-base 240 and/or base 232 is preferably providedwith indexing stops 250 to positively position the sub-base 240 withrespect to the base 232. For example, if four tip cassettes 242 arepositioned on the sub-base 240, the sub-base and/or the base 232 willinclude four indexing stops 250 to positively position each cassetteover the array of cylindrical bores 234 in the base 232. Such stops 250can simply consist of alignment holes formed in the sub-base 240 andbase 232, as shown in FIG. 25. A pin (not shown), for example, can alsobe inserted in the alignment holes to hold the sub-base in position.

Formed through the tip cassette 242 is an array of holes 244, which aresized to respectively receive a disposable protective tip 84, with therim 85 of the tip resting on the upper surface of the cassette. Thespacing and arrangement of the holes 244 in the tip cassette 242coincides with the spacing and arrangement of the pins 47 supported onthe head assembly 38 and the spacing and arrangement of the cylindricalpiston bores 234 of the tip insertion base 232. Again, the drawings showa preferred 4×3 array.

Operation of the tip loading station 230 is similar to that describedabove. In particular, once a loaded cassette 242 has been positionedabove the piston bores 234 of the base 232, the head assembly 38 of theprimary magnet unit 18 is positioned above the tip cassette by the y andz stepper motors 42 and 44 and then gently brought down in thez-direction until the ends of the pin bodies 45 are in close proximityto the disposable tips 84. The tips 84 to be loaded can then be enteredin the control unit 24, whereby a burst of air pressure supplied throughthe respective air supply connector 236 will drive the selected tiploading pistons 238 upwardly into the bores 244 of the tip cassette 242to force the tips 84 upwardly out of the cassette to frictionally engagethe pin bodies 45. Release of the air pressure will return the pistons238 down into the base 232, whereby the sub-base 240 can be translatedto move another tip cassette 242 over the piston bores 234 to repeat theprocess.

FIG. 26 shows an alternative embodiment of a magnet actuator system 260,wherein the tension springs 71 provided in the bores 67 of the pistonhousing 69 for biasing the magnet rods 66 in an upward position havebeen replaced by permanent magnets 262. In particular, a permanentmagnet 262 is fixed within each bore 67 of the piston housing 69 tomagnetically attract the ferromagnetic piston 65 fixed at the end of themagnet rod 66.

When not magnetically engaged with a solenoid electromagnet 61, theferromagnetic piston 65 will be magnetically retained by the permanentmagnet 262 in an upward position within its respective bore 67 of thepiston housing 69, as illustrated by the left-most piston 65 shown inFIG. 26. However, upon activation, the solenoid electromagnet 61 willcounteract the magnetic force applied by the permanent magnet 262 andwill pull the piston 65 away from the permanent magnet when moved intoproximity with the piston. Activated electromagnets 61 pulling pistons65 away from the permanent magnets 262 are illustrated by the threeelectromagnets on the right side of FIG. 26.

It has been found that the initial force needed to disconnect the piston65 from the permanent magnet 262 can be achieved by applying a voltageof about 12-15V to the electromagnet 61. Once the piston 65 has beenpulled free from the permanent magnet 262, this force can be drasticallyreduced, wherein application of only 6V to the electromagnet 61 isrequired. Such reduction of voltage applied to the electromagnet 61results in a reduction of heat produced by the solenoid electromagnetand reduces the wear on the electromagnet.

Also shown in FIG. 26, and in additional detail in FIG. 27, is theconnection between the magnet rod 66 and the ferromagnetic piston 65according to a preferred embodiment of the present invention. Inparticular, the ferromagnetic piston 65 preferably includes a magnetretractor 270, a washer 272, an O-ring 274 and a cone fitting 276. Themagnet retractor 270 and the cone fitting 276 are made from aferromagnetic material to be respectively attracted by the permanentmagnet 262 and the solenoid electromagnet 61.

The cone 276 includes a proximal end 278 having an aperture 280 formedtherein for receiving the end of the magnet rod 66. The distal end 282of the cone 276 opposite the proximal end 278 is preferably conical inshape to facilitate seating of the piston 65 within its respectivepiston bore 67 of the piston housing 69. The distal end 282 furtherincludes a bore 284 communicating with the magnet rod aperture 280. Thedistal end bore 284 is sized to receive the O-ring 274, the washer 272and a proximal end 286 of the magnet retractor 270. In this regard, theouter surface of the proximal end 286 of the magnet retractor 270 andthe inner surface of the cone bore 284 are preferably provided withmating threads so that the retractor and the cone 276 can be threadablyengaged to form the piston 65.

Upon assembly, the magnet rod 66 is slipped through the aperture 280formed in the proximal end 278 of the cone 276. The O-ring 274 has aninner diameter matching the outer diameter of the magnet rod 66 and isslipped over the end of the rod extending into the cone. The washer 272is placed on top of the O-ring 274 and the magnet retractor 270 isthreaded into the bore 284 to compress the O-ring. As the O-ring 274 iscompressed, it expands radially inward to grip the outer surface of themagnet rod 66. Such gripping force is sufficient to firmly retain therod 66 to the piston 65.

As a result of the present invention, a three axis transfer devicecontrol system is provided which enables the separation and transfer ofany desired combination of samples with the advantage of executingmultiple tests in a single run. The design offers significant advantagesin addition to the accuracy of movement, reliability, reduction in costof the process and efficiency. The flexibility of the system due to theseveral modes of operation (combinatorial functionality) allows thesystem to be operated as a fixed transfer device with the capability ofbreaking the array into smaller sub-arrays.

The system according to the present invention is ideally suited for avariety of analytical applications involving samples, such as DNA,proteins, peptides, hormones etc. The system according to the presentinvention is further well adapted to conduct false positive testing ofsamples, which is an essential step performed in all medical labs. Insuch a procedure, the system of the present invention will captureexpensive magnetic reagents in those wells that had negative testresults and, after washing with a fresh washing liquid, the magneticreagents will then be ready for another set of samples instead of beingdiscarded.

Such a procedure can be conducted as follows. First, all wells that showa binding surface reaction to the magnetic particles and the target gene(i.e., a positive result) are located. It should be noted that thenon-reactive particles in the non-positive wells could now be capturedand washed, or the process can proceed later after the below proceduresare completed.

Next, the controller of the present invention is activated to engage thepin units on the “positive” reacted wells. The pin units that areengaged will capture the magnetic particles in the “positive” wells andmove the positive particles to new wells, which contain a washingliquid. Preferably, these positive colored particles are divided intotwo groups, so that half is in one well and the other half is in asecond well. As a result, a control well and a test well areestablished.

The control well is left alone and the “test” well's particles arewashed according to the combinatorial washing process described above.The washing will determine whether there is a “real” positive or a“false” positive. In particular, if the binding stays intact, it is areal positive and if the washing strips off the non-specific boundcolored reagent, it is a “false” positive.

To determine the color level in both the control and the newly washedtest, a camera or visual inspection can be utilized. With camerainspection, a computer system can be implemented to compare the initialcolor level of the control with the washed tests. If there is adifference in the color, there is a “false” positive. To insure that the“false” positive is truly a false result, the process is repeated withfresh new particles and with a fresh small amount from the originalsample(s) that gave the false positive.

For example, with a ninety-six well plate, if four wells were determinedto be positive and ninety-two were negative (i.e., the magneticparticles did not react with the samples in ninety-two wells), the pinsfor these ninety-two wells are selected to carry out magnetic separationin these wells. This will constitute the first cleaning and washing.Then, an extensive washing sequence can be carried out, wherein eachwash is done with a fresh washing liquid. This will effectivelyeliminate any contaminants from these wells.

While the system of the present invention has been primarily describedherein as a system utilizing magnetic forces for attracting andreleasing magnetic particles, those skilled in the art will appreciatethat the three axis coordinate control system of the present inventionmay also be employed to control movement of an array of pipettes orother transferring devices to transfer samples from one or more sourcevessels to one or more target vessels using known techniques. Such adevice is intended to come within the scope of the invention. Inparticular, as mentioned herein, the system may simply include a vesseldrive unit including a translatable support plate for supporting thesource vessel and the target vessel thereon and a support plate drivefor reciprocally translating the support plate in an x-direction. Also,in this case, the primary magnet unit would simply be termed a primarytransfer unit and would include at least one transfer device.

Although the preferred embodiments of the present invention have beendescribed with reference to the accompanying drawing, it is to beunderstood that the invention is not limited to those preciseembodiments, and that other changes and modifications may be made by oneskilled in the art without departing from the scope or spirit of theinvention.

1. A transfer device for transferring a sample from a source vessel to atarget vessel, the transfer device comprising: a pin tip having acentral bore terminating at a bottom wall; an actuating element movablydisposed in said pin tip bore between a first position adjacent said pintip bottom wall and a second position away from said bottom wall, saidmovement of said actuating element causing a sample in proximity to saidpin tip to be alternately collected and released from said pin tip; anactuator rod for moving said actuating element between said first andsecond positions, said actuator rod defining a stroke length associatedwith said movement; and a compensating device connected between saidactuating element and said actuator rod for compensating for anyvariations in said actuator rod stroke length.
 2. A transfer device asdefined in claim 1, wherein said actuating element is a magnet, andwherein a magnetic force is applied at said pin tip bottom wall whensaid magnet is at said first position and said magnetic force is removedfrom said pin tip bottom wall when said magnet is moved to said secondposition.
 3. A transfer device as defined in claim 1, wherein saidcompensating device urges said actuating element into contact with saidpin tip bottom wall at said first position.
 4. A transfer device asdefined in claim 3, wherein said compensating device comprises aresilient element for biasing said actuating element against said pintip bottom wall at said first position.
 5. A transfer device as definedin claim 3, wherein said compensating device comprises a tubular memberhaving a central bore and a spring disposed within said bore, saidactuating element being fixed at one end of said tubular member and saidactuator rod movably extending into said central bore to engage saidspring.
 6. A transfer unit for transferring a sample from a sourcevessel to a target vessel, the transfer unit comprising: a headassembly; a transfer device supported on said head assembly, saidtransfer device having a tip removably attached to an end thereof; and atip ejector supported on said head assembly for removing said tip fromsaid transfer device.
 7. A transfer unit as defined in claim 6, whereinsaid tip ejector comprises: an ejector plate having an aperture definedby an edge, said transfer device extending through said aperture; and adrive supported on said head assembly and connected to said ejectorplate for moving said ejector plate away from said head assembly,wherein said aperture edge engages said tip attached to said transferdevice to remove said tip from said transfer device upon movement ofsaid ejector plate away from said head assembly.
 8. A transfer unit asdefined in claim 6, wherein said tip has a central bore terminating at abottom wall and said transfer device further comprises: an actuatingelement movably disposed in said tip bore between a first positionadjacent said tip bottom wall and a second position away from saidbottom wall, said movement of said actuating element causing a sample inproximity to said tip to be alternately collected and released from saidtip; an actuator rod for moving said actuating element between saidfirst and second positions, said actuator rod defining a stroke lengthassociated with said movement; and a compensating device connectedbetween said actuating element and said actuator rod for compensatingfor any variations in said actuator rod stroke length.
 9. A transferunit as defined in claim 8, wherein said actuating element is a magnet,and wherein a magnetic force is applied at said tip bottom wall whensaid magnet is at said first position and said magnetic force is removedfrom said tip bottom wall when said magnet is moved to said secondposition.
 10. A transfer unit as defined in claim 8, wherein saidcompensating device urges said actuating element into contact with saidtip bottom wall at said first position.
 11. A transfer unit as definedin claim 10, wherein said compensating device comprises a resilientelement for biasing said actuating element against said tip bottom wallat said first position.
 12. A transfer unit as defined in claim 10,wherein said compensating device comprises a tubular member having acentral bore and a spring disposed within said bore, said actuatingelement being fixed at one end of said tubular member and said actuatorrod movably extending into said central bore to engage said spring. 13.A transfer unit as defined in claim 6, further comprising: a supportingframe movably supporting said head assembly; and a tip loading stationsupported on said frame for loading said tip onto said transfer device.14. A transfer unit as defined in claim 13, wherein said tip loadingstation comprises: a base having a bore formed therein, said bore havinga proximal end terminating at an upper surface of said base and a distalend; a sub-base supported on said upper surface of said base, saidsub-base supporting said tip for application to said transfer device;and a pressure source connected to said distal end of said base bore forapplying a pressure through said base bore for forcing said tip fromsaid sub-base onto said transfer device.
 15. A transfer unit as definedin claim 14, wherein said base further includes a piston slidablyreceived within said base bore, said piston being driven by saidpressure applied by said pressure source to force said tip from saidsub-base onto said transfer device.
 16. A transfer unit as defined inclaim 14, wherein said sub-base is adapted to support a plurality oftips and is translatable with respect to said base to positivelyposition said tips over said base bore.
 17. A transfer unit as definedin claim 14, wherein said tip loading station further comprises a tipcassette supported on said sub-base, said tip cassette having a boreformed therethrough, said bore being sized to receive said tip andhaving a distal end terminating at said upper surface of said base. 18.An apparatus for transferring a sample from a source vessel to a targetvessel comprising: a transfer unit including a transfer device fortransferring a sample; a supporting frame movably supporting saidtransfer unit; and a tip loading station supported on said supportingframe for loading a tip onto an end of said transfer device.
 19. Anapparatus as defined in claim 18, wherein said tip loading stationcomprises: a base having a bore formed therein, said bore having aproximal end terminating at an upper surface of said base and a distalend; a sub-base supported on said upper surface of said base, saidsub-base supporting said tip for application to said transfer device;and a pressure source connected to said distal end of said base bore forapplying a pressure through said base bore for forcing said tip fromsaid sub-base onto said transfer device.
 20. An apparatus as defined inclaim 19, wherein said base further includes a piston slidably receivedwithin said base bore, said piston being driven by said pressure appliedby said pressure source to force said tip from said sub-base onto saidtransfer device.
 21. An apparatus as defined in claim 19, wherein saidsub-base is adapted to support a plurality of tips and is translatablewith respect to said base to positively position said tips over saidbase bore.
 22. An apparatus as defined in claim 19, wherein said tiploading station further comprises a tip cassette supported on saidsub-base, said tip cassette having a bore formed therethrough, said borebeing sized to receive said tip and having a distal end terminating atsaid upper surface of said base.
 23. A transfer unit for transferring asample from a source vessel to a target vessel comprising: a transferdevice having a hollow body and an actuating element movably disposed insaid hollow body between a first and a second position, said movement ofsaid actuating element causing a sample in proximity to said transferdevice to be alternately collected and released from said transferdevice; an actuator plate having at least one individually activatedelectromagnet disposed thereon; an actuator plate drive for reciprocallytranslating said actuator plate; an actuator rod having a first end anda second end, said first end connected to said actuating element in saidhollow body of said transfer device; a ferromagnetic piston disposed onsaid second end of said actuator rod, said piston being engageable withsaid electromagnet when said electromagnet is activated for moving saidactuating element from said first position to said second position upontranslation of said actuator plate; and a piston housing spaced fromsaid actuator plate, said piston housing including a magnet for biasingsaid piston toward said piston housing.
 24. A transfer unit as definedin claim 23, wherein said actuating element of said transfer device is amagnet slidably disposed within said hollow body between said firstposition adjacent a tip of said transfer device, wherein a magneticforce is applied at said tip, and said second position away from saidtip, wherein said magnetic force is removed from said tip foralternately collecting and releasing samples from said transfer device.25. A transfer unit as defined in claim 23, wherein said pistoncomprises: a ferromagnetic cone fitting having an aperture formed in aproximal end thereof for receiving said second end of said actuator rodand a bore formed in a distal end thereof; an O-ring disposed in saidcone fitting bore around said second end of said actuator rod; and aferromagnetic retractor fitted in said cone fitting bore for compressingsaid O-ring into gripping engagement with said actuator rod.